With an ambitious global agenda to scale up integrated interventions for more than 1 billion people living in 56 developing countries where multiple neglected tropical diseases (NTDs) are coendemic, we need to carefully consider the specter of resistance and other forms of drug failure. Of the six possible different drugs contained in the rapid-impact package—azithromycin, praziquantel, albendazole or mebendazole, and diethylcarbamazine or ivermectin—the agents albendazole and mebendazole particularly stand out as drugs that could induce resistance. To create a truly robust pipeline of NTD drugs, we need to look to either small biopharmaceuticals or a new generation of NTD product development partnerships (PDPs). Many of the NTD PDPs are funded in part by the Bill & Melinda Gates Foundation. With genomes completed for a large number of NTD pathogens, including the agents that cause Chagas disease, human African trypanosomiasis, leishmaniasis, leprosy, leptospirosis, lymphatic filariasis (LF), schistosomiasis, and trachoma, it should be theoretically possible to mine bioinformatics databases in order develop a large number of antipoverty vaccines in the coming decade. The global control and elimination of the NTDs will require mechanisms to introduce new health products, e.g., vaccines, drugs, and diagnostics, together with existing drugs, in order to create new-generation rapid-impact packages. This approach will be necessary for sustainably reducing poverty and for meeting Millennium Development Goal targets.